Ivacaftor for patients with cystic fibrosis

Abstract

Ivacaftor is an oral bioavailable potentiator of the cystic fibrosis transmembrane conductance regulator protein. It is the first therapeutic agent that has been registered for clinical use which targets the basic defect in people with cystic fibrosis who carry a G551D mutation or other rarer specific gating mutations. Clinical trials have shown consistent and impressive clinical benefit that appears to be sustained over time in people with cystic fibrosis who carry a G551D mutation and similar benefits have been seen in those who carry rarer gating mutations. Ivacaftor is orally administered twice daily with a dose that does not vary between children aged 6 years through to adult life in patients with G551D. It appears to be well tolerated although there are potential interactions with drugs that are metabolised through CYPP450 CYP3A. Ivacaftor is also currently being trialled in combination with correctors for patients with the most common mutation of cystic fibrosis transmembrane conductance regulator the F508del mutation.

Keywords::

• CFTR modulator
• cystic fibrosis
• gating mutation
• ivacaftor
• potentiator therapy

Financial & competing interests disclosure

The author has been an investigator on many of the Vertex Pharmaceutical Inc sponsored trials and the author’s institution has received funding on a per patient basis to enable participation in the trials. The author has received travel and accommodation to attend clinical meetings and sat on Vertex Pharmaceutical advisory boards and the author’s institution has received honoraria for consultancy work. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Clinical trial data support the use of ivacaftor in patients aged 6 years and older with cystic fibrosis carrying one copy of G551D mutation.

• The use of ivacaftor in other specific gating mutations (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D) appears to carry a similar benefit.

• The potential benefit of ivacaftor in combination therapies with other cystic fibrosis transmembrane conductance regulator (CFTR) mutations that are primarily not gating to enhance CFTR modulation awaits clinical trial evidence.

• Ivacaftor is well tolerated, and to date there are no serious safety signals. Upper airway symptoms are more common in patients taking ivacaftor.

• Ivacaftor is very expensive, and managing the costs of CFTR modulator therapy and indeed new therapies in relatively rare genetic diseases in the future needs to be considered.